Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function


Nature communications


Jami, S., Deuis, J. R., Klasfauseweh, T., Cheng, X., Kurdyukov, S., Chung, F., Okorokov, A. L., Li, S., Zhang, J., Cristofori-Armstrong, B., Israel, M. R., Ju, R. J., Robinson, S. D., Zhao, P., Ragnarsson, L., Andersson, Å., Tran, P., Schendel, V., McMahon, K. L., … Vetter, I. (2023). Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function. Nature Communications, 14(1).



Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons.

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